In the last year, we have focused our study on 1)the phenotype of rare obesity variants; 2)the predictive value of commonly used tests to assess insulin sensitivity; and 3)the incretin response in healthy volunteers and insulin resistant subjects over different ethnic and racial backgrounds. Rare Obesity Variants Patients with rare obesity variants including Dercum's disease, multiple symmetric lipomatosis (Madelungs disease) and severe lipedema are currently being recruited for study. These are overlapping, heterogeneous conditions that most often manifest in adulthood and usually occur in the setting of generalized obesity. Dercum's disease is notable for painful adipose tissue and lymphedema. There are familial forms of each of these conditions although no consistent genetic defect has been found. Clinical care for these patients has been largely symptomatic including excision of painful lipomas and treatment of lymphedema. Using genetic techniques, we plan to study the pathways that are modified in the fat of these patients with unique phenotypes and apply whole exome sequencing to determine the genetic cause in families that carry these traits. Impact of Race and Ethnicity on Commonly Used Measurements of Insulin Sensitivity African Americans are highly prone to develop diabetes. It is widely accepted that insulin resistance is a major predisposing factor. Consequently, accurately quantifying insulin sensitivity/resistance is important in this population. Among the many available methods for measuring insulin sensitivity in humans, the hyperinsulinemic euglycemic glucose clamp is widely accepted as the reference method because it directly measures whole body glucose disposal at a given level of insulinemia under steady-state conditions. However, the glucose clamp is labor intensive, technically demanding, and time consuming, making it impractical for use in large epidemiological and clinical studies. As a consequence, a number of simple surrogate indices of insulin sensitivity/resistance derived from fasting blood insulin and glucose concentrations e.g., quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment (HOMA), 1/fasting insulin or oral glucose tolerance tests have been developed. These surrogate indices are extensively employed in large clinical, epidemiological, and interventional studies. However, ethnicity and BMI may affect validity of fasting-based surrogate indices of insulin sensitivity. In fact, recent studies suggest major limitations in fasting and OGTT-derived indices of insulin sensitivity in individuals of African descent. Multiple studies, solely on the basis of FSIVGTT and OGTT, have reported higher insulin resistance in non-diabetic adults and children of African heritage than those of a European-based ethnicity. In a recent study, a hyperinsulinemic-euglycemic clamp done in parallel with OGTT was discrepant in healthy, non-diabetic African Americans; whereas direct measurement of glucose disposal rate by hyperinsulemic-euglycemic clamp was identical between the African- and European-American. The specific aim of this study is to measure total body insulin sensitivity as reflected by glucose disposal during hyperinsulinemic-euglycemic clamp and to delineate basal hepatic insulin sensitivity by measuring fasting hepatic glucose production (assessed after a steady state infusion of deuterium glucose as tracer 6,62H2 glucose). The glucose disposal will be compared to the SI insulin sensitivity index by mathematical modeling of plasma insulin and glucose measurements obtained during FSIVGTT using the Bergman minimal model among people of African and European descent. Similarly, the study investigated differences in insulin sensitivity in Hispanics and South Asians. Both these populations have high risk for developing diabetes. Insulin sensitivity and beta cell function was measured during IVGTT and mixed meal tolerance tests. Incretin effect The term incretin effect (INtestinal seCRETion of INsulin) was coined to describe the observation that oral glucose administration induces a more robust insulin response when compared to an isoglycemic intravenous glucose infusion. Glucagon like peptide 1(GLP-1) and Glucose dependent Insulinotropic peptide (GIP) are intestinal hormones released in response to oral food intake which in turn stimulate pancreatic beta-cells to release insulin and thus are responsible for part of the incretin effect. Impaired incretin effect due to reduced islet responses to the incretin hormones, is an early and frequently observed abnormality in dysglycemic and insulin resistant states. Traditionally, incretin effect has been measured using an isoglycemic clamp technique where a fixed oral glucose load is given on first day of testing. On the second day, isoglycemic intravenous glucose is infused to match the blood glucose measurements during the oral glucose load. Our approach uses a 1-day procedure by giving an oral glucose load during a hyperglycemic clamp. Insulin response after the oral glucose load is used to calculate the incretin effect. Measuring incretin effect in African Americans and South Asians is necessary to understand the pathophysiology of pancreatic beta cell function and to study the effects of various interventions on beta-cell dysfunction.